Download formulation and evaluation of domperidone loaded mineral oil

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 68 No. 1 pp. 121ñ126, 2011
ISSN 0001-6837
Polish Pharmaceutical Society
FORMULATION AND EVALUATION OF DOMPERIDONE LOADED
MINERAL OIL ENTRAPPED EMULSION GEL (MOEG) BUOYANT BEADS
INDERBIR SINGH1*, PRADEEP KUMAR2, HARINDERJIT SINGH1, MALVIKA GOYAL1
and VIKAS RANA3
Chitkara College of Pharmacy, Chandigarh-Patiala National Highway,
Rajpura-140401, Patiala, Punjab, India
2
Department of Pharmacy and Pharmacology, Division of Pharmaceutics, University of the Witwatersrand,
Johannesburg, South Africa
3
Department of Pharmaceutical Sciences and Drug Research, Punjabi University,
Patiala-147002, Patiala, Punjab, India
1
Abstract: Alginate based mineral oil entrapped emulsion gel (MOEG) buoyant beads of domperidone were prepared by emulsion gelation technique. The prepared beads were evaluated for particle size, surface morphology, buoyancy, actual drug content and entrapment efficiency. Effect of different oils (castor oil, olive oil and
linseed oil) and oil concentrations (10%, 15% and 20%, w/w) on uniformity, homogeneity and integrity of the
beads was also studied. Density of the formulated beads was found to be ranging between 0.101 and 0.182
g/cm3. The results of the in vitro drug release indicated that linseed oil showed to be good release retardant compared to castor oil and olive oil. Moreover, the beads formulated using 15%, w/w linseed oil were more uniform in shape, exhibited maximum buoyancy and minimal oil leakage. Diffusion exponent (n) value varied
from 0.4855 to 0.7710 indicating anomalous drug release behavior involving swelling, diffusion and/or erosion
of the polymer matrix.
Keywords: MOEG beads, domperidone, emulsion gelation, buoyancy
windows, reduced dosing and increased patient
compliance, reduced Cmax and improved safety profile for the drug with side effect associated with
Cmax. Various approaches to induce buoyancy in
cross linked beads are reported, which include
freeze-drying, entrapment of gas or gas forming
agents and use of volatile oils or fixed oils (2, 3).
Domperidone is a dopamine D2 receptor antagonist and is used as a prokinetic agent for treatment
of upper gastrointestinal motility disorders (4). After
oral administration, domperidone is rapidly
absorbed from the stomach and the upper part of the
gastrointestinal tract (GIT) with fewer side effects.
It is a weak base with good solubility in acidic pH
but significantly reduced solubility in alkaline medium (5).
The present investigation was designed to formulate and evaluate mineral oil entrapped emulsion
gel (MOEG) buoyant beads of sodium alginate as
delivery system of domperidone. The drug loaded
beads were prepared by emulsion gelation technique
Oral sustained drug delivery system is complicated by limited gastric residence time. Rapid gastrointestinal transit can prevent complete drug
release in absorption zone and reduce the efficiency
of administered dose because a majority of the drug
is absorbed in stomach or upper part of small intestine. The controlled gastric retention of solid dosage
form may be achieved by mucoadhesion, floatation,
sedimentation, expansion, modified shape system
and simultaneous administration of pharmacological
agents (1). Gastro-retentive floating drug delivery
system has bulk density lower than gastric fluid and
thus remains buoyant in the stomach without affecting the gastric emptying rate for prolonged period of
time. While the system is floating on the gastric content, the drug is released slowly at desired rate from
the system. Floating drug delivery systems offer
important advantages as they are less prone to gastric emptying resulting in reduction in intra and inter
subject variability in plasma drug levels, effective
for the delivery of the drug with various absorption
* Corresponding author: e-mail: [email protected]; [email protected]; phone: 91-9855024140
121
122
INDERBIR SINGH et al.
using castor oil, olive oil and linseed oil in different
concentrations (10%, 15% and 20%, w/w). The formulated beads were evaluated for particle size, surface morphology, density, actual drug content,
encapsulation efficiency, buoyancy, uniformity,
integrity and in vitro drug release.
w/w) CaCl2 solution at room temperature. The emulsion gel beads were allowed to stand in the solution
for 60 min before being separated and washed with
distilled H2O. The beads were dried under vacuum
at ambient temperature and were stored in desiccator. The composition of different batches of the drug
loaded alginate beads are given in Table 1.
EXPERIMENTAL
Materials
Domeperidone was received as a gift sample
from Helios Pharmaceuticals, India. Sodium alginate
was purchased from Qualigens Fine Chemicals, India.
Olive oil, castor oil and linseed oil were procured from
Yarrow Chemicals, India. Calcium chloride was purchased from Loba Chemicals, India. All other chemicals were of analytical grade and were used as such.
Methods
Preparation of domperidone loaded sodium alginate MOEG beads
Doperidone loaded MOEG beads were prepared by emulsion gelatin method (6). In this
method pre gelation liquid of sodium alginate solution (2%, w/v) was prepared. Mineral oil in the concentration (10%, 15% and 20%, w/w) was then
added to the polymer solution. To ensure emulsion
stabilization, the mixtures were homogenized at
10000 rpm using a homogenizer (Remi-motors, RQ122, Vasai , India ) for 20 min with the addition of
emulsifier Span 80. Domperidone was then dispersed in the formed emulsion in the fixed
drug:polymer ratio (1:1, w/w). The bubble free
emulsion was extruded, using a 20 gauge syringe
needle into 100 mL of gently agitated 0.1 M (1%,
Study of homogeneity and uniformity/integrity of
beads
In order to achieve uniformity in bead size and
density it is essential that synthesis conditions such
as viscosity, rate of falling of drops, stirring rate and
distance between syringe and emulsion medium, be
maintained constant during the course of formation
of beads. Variation in any of these parameters during the bead formation process may result in the production of non homogeneous and non uniform
beads, affecting the overall results to an appreciable
extent (7). All the formulated batches of MOEG
buoyant beads were visually analyzed for oil leakage, shape and color.
Particle size of the prepared MOEG beads was
determined using an optical microscope (Model CH20i, Olympus Pvt. Ltd., India) fitted with the stage
and an ocular micrometer. Twenty dried beads were
measured for calculating the mean diameter of
beads. The result is expressed as the mean diameter
(mm) ± standard deviation.
Density measurements
The mean weight and diameter of MOEG
beads were measured and used to mathematically
calculate the densities of the spherical sodium alginate beads using the following equation:
Table 1. Composition and physiochemical properties of sodium alginate MOEG beads.
Formulation
Code
Oil
Concentration
(% w/w)
Mean Diameter
(mean ± SD)
(mm)
Density
(g/cm3)
Actual Drug
Content (%)
(AC)
Entrapment
Efficiency (%)
(DEE)
FC1
10
0.92 ± 0.06
0.182
48.54 ± 0.84
92.41 ± 1.37
FC2
15
0.90 ± 0.07
0.175
49.29 ± 1.05
95.64 ± 1.88
FC3
20
0.98 ± 0.04
0.160
48.55 ± 0.72
97.11 ± 1.45
FO1
10
0.95 ± 0.03
0.177
48.92 ± 0.66
93.55 ± 1.81
FO2
15
1.02 ± 0.04
0.154
49.25 ± 0.95
96.80 ± 2.25
FO3
20
1.05 ± 0.05
0.150
49.08 ± 0.78
94.12 ± 1.75
FL1
10
0.88 ± 0.08
0.122
50.33 ± 0.84
89.64 ± 2.31
FL2
15
1.10 ± 0.05
0.101
50.14 ± 0.99
96.50 ± 1.01
FL3
20
NA
NA
47.47 ± 1.88
95.92 ± 1.54
123
Formulation and evaluation of domperidone loaded mineral oil entrapped emulsion gel...
Table 2. Some parameters studied on MOEG beads.
Formulation
Code
Buoyancy
%
Oil Leakage
Shape
Color of Beads
FC1
Not Floating
Yes & Highest
Spherical
Off White
FC2
40 % Floating
Yes
Spherical
Off White
FC3
35 % Floating
Yes & Highest
Spherical with tailing
Off White
FO1
Not Floating
Intermediate (Less than
castor oil)
Spherical and sticky
Yellowish
FO2
30 % Floating
Intermediate
Spherical and sticky
Light Yellow
FO3
80 % Floating
Intermediate
Spherical and sticky
Light Yellow
FL1
100 % (max.) Floating
Minimum (Less than both
castor oil and olive oil)
Spherical & least sticky
Yellowish
FL2
100 % (max.) Floating
Minimum
Spherical
Yellowish white
FL3
75 % Floating
Minimum
Distorted shape
Light Yellow
Table 3. Kinetic studies on MOEG beads.
Zero order
First order
Higuchi
Batch
No.
r2
k0 (h-1)
r2
k1 (h-1)
r2
FC1
0.6398
0.1437
0.8561
-0.0029
FC2
0.7025
0.2928
0.9710
-0.0116
Korsmeyer-Peppas
kH (h-/2)
r2
n value
kKP (h-n)
0.7697
4.354
0.8664
0.5182
0.7034
0.8566
7.6832
0.8981
0.5457
0.8373
FC3
0.6629
0.1462
0.8876
-0.0030
0.7384
3.2674
0.8348
0.4855
0.8532
FO1
0.8835
0.3278
0.8483
-0.0069
0.9754
6.5681
0.9542
0.6675
0.4531
FO2
0.7601
0.3256
0.9272
-0.0095
0.9132
8.3887
0.9364
0.6289
0.6536
FO3
0.8025
0.0376
0.9423
-0.0004
0.9139
1.3174
0.9433
0.5391
0.1635
FL1
0.9148
0.2591
0.9488
-0.0072
0.9835
6.7438
0.9619
0.5783
0.7930
FL2
0.8634
0.3843
0.9551
-0.0118
0.9764
9.3499
0.9732
0.7710
0.3067
D = M/V
where V = 4/3πr3 (for a typical sphere), D is the density of MOEG beads, M is the weight of beads, V is
the volume of beads and r is the radius of beads.
Determination of the beads buoyancy
The MOEG beads (n = 20) were kept in a
beaker filled with 50 mL of 0.1 M HCl (pH = 1.2).
The floating ability of beads was measured by visual observation for the overall time period of 6 h
(after 2 h each). The beads that floated on the surface of the medium and those that settled down at
the bottom were recovered separately and the floating percentage (% buoyancy) was estimated (8). The
integrity of the beads was also observed visually
during the buoyancy test.
Determination of actual drug content and entrapment efficiency
An accurately weighed amount of 50 mg of
domperidone loaded MOEG beads was dissolved in
100 mL of 0.1 M HCl solution. It was stirred for 6 h
using magnetic stirrer (MICROSIL, MLH-1, India).
The resulting solution was then filtered and the filtrate was suitably diluted. Domperidone content was
determined spectrophotometically (Systronics 2202
Spectrophotometer, India) at 284 nm. Actual drug
content (AC) and entrapment efficiency (EE) were
calculated according to the following equations:
AC (%) = Mact / Mms ◊ 100
EE (%) = Mact / Mthe ◊ 100
where Mact is the actual drug content in MOEG
beads, Mms is the weighed quantity of beads and Mthe
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INDERBIR SINGH et al.
carried out using a scanning electronic microscope
(SEM- JEOL MODEL 8404; Japan at magnification
of 500◊) equipped with secondary electron at an
accelerating voltage of 10 kV. The sample beads
were mounted on metal grids using double sided
tape coated with gold to a thickness of about 30 mm
in vacuum evaporator.
Figure 1. SEM micrograph of drug loaded MOEG bead
Figure 2. SEM micrograph of the surface of MOEG bead
In vitro domperidone release studies
In vitro release studies were carried out on drug
loaded MOEG buoyant beads using USP 24 dissolution test apparatus I. The weighed quantity of beads
equivalent to 100 mg of domperidone were introduced into dissolution basket and the basket was
placed in 900 mL simulated gastric fluid (pH 1.2)
maintained at 37 ± 0.5OC and 50 rpm. Aliquots of 5
mL solution were withdrawn at predetermined time
intervals and replaced by fresh dissolution mediums.
The withdrawn samples were analyzed for domperidone content spectrophotometrically (Double beam
spectrophotometer, Systronics 2202, India) at 284
nm.
Statistical analysis of data
The experimental results were expressed as the
mean ± standard deviation. Studentís t-test was
applied to determine the level of significance. The
analysis of variance (ANOVA) was also applied to
check significance difference in the drug release
from different formulations. Difference was considered statistically significant when p < 0.05.
RESULTS AND DISCUSSION
Figure 3. Optical photo micrograph of MOEG beads
is the theoretical amount of the drug in the beads
calculated from the quantity added in the process.
All analyses were carried out in triplicate.
Scanning electron microscopy (SEM)
Morphological examination of the surface and
the internal strength of the dried MOEG beads were
Particle size and morphology/uniformity of beads
The mean diameters of domperidone loaded
Na alginate MOEG beads are shown in Table 1. In
fact, small values of standard deviation revealed in
Table 1 confirmed high process uniformity regarding homogenization efficiency and low variability in
processing conditions. The results in Table 1 reveals
that the mean diameter of beads range between 0.92
± 0.06 ñ 1.10 ± 0.05. Moreover, beads size was
found to increase with an increase in oil concentration, irrespective of the type of oil used. This might
be due to an increase in the droplet viscosity caused
by higher oil content. Increased viscosity along with
involvement of gravitational forces may lead to an
increase in emulsion droplet size leading to larger
bead formation. The scanning electron micrographs
(SEM) and optical micrographs of the domperidone
loaded MOEG beads are illustrated in Figs. 1ñ3,
respectively. Beads were found to be well rounded
spheres with uniform size distribution under optical
Formulation and evaluation of domperidone loaded mineral oil entrapped emulsion gel...
microscope. It can be revealed from SEM that the
formulated MOEG beads were discrete and spherical in shape with rough outer surface along with
pores or channels that might form passage to help
the drug release from the inner part of the beads.
Some domperidone crystals were also seen on the
surface of the beads which might be present because
of leaching out of the drug to the surface during drying and subsequent shrinkage. Beads prepared using
castor oil and olive oil in different concentration
were less acceptable in terms of shape and stickiness. Amongst the formulated batches of the MOEG
beads linseed oil in 15 % concentration was found to
be the best in terms of shape and stickiness.
Moreover, oil leakage and color change were also
found to be minimal in the batches formulated with
linseed oil (FL1, FL2, and FL3).
125
Figure 4. Release profile of domperidone from MOEG beads in
0.1 M HCl (pH 1.2)
Density measurements
Density values of the MOEG beads formulated
using castor oil, olive oil and linseed oil ranged from
0.182 to 0.160, 0.177 to 0.150 and 0.122 to 0.101
g/cm3, respectively. Table 1 shows that calculated
densities of all the MOEG beads were less than the
density of 0.1 M HCl (i.e., 1.004 g/cm3) imparting
their flotation. Results of lower densities obtained in
the presence of higher oil concentrations are in line
with results reported by Elmowafy et al. (8).
Determination of the beads buoyancy
The bead buoyancy data shown in Table 2 indicated the dependence of floating ability of the beads
on the oil concentration. Instantaneous in vitro floating behavior was observed for drug loaded MOEG
beads and lasted for at least 6 h except for FC1 batch
which was not floating. Overall, FC and FO showed
lesser buoyancy compared with FLI and FL2 batches. This might be due to lesser symmetry in shape
and probably oil leakage from the formulation leading to unequal forces of released medium (0.1 M
HCl) on their surfaces. The beads with higher concentration of oil were more flotable than those with
lower concentrations of the oil. This may be attributed to a decrease in density of the beads with an
increase in oil concentration.
Determination of actual drug content and drug
entrapment efficiency
The effect of changing oil type and oil concentration on the drug loaded MOEG beads is shown in
Table 1. Drug entrapment ranged from 89.64 to
98.92% depending upon the composition of the nine
batches of MOEG beads of domperidone. A higher
proportion of oil in the beads increased the drug
Figure 5. Higuchi release model for domperidone release from
MOEG beads
Figure 6. Korsmeyer-Peppas model for mechanism of drug release
from MOEG beads
126
INDERBIR SINGH et al.
entrapment efficiency in different batches, which
could be attributed to partitioning of the drug in the
oil phase. A direct correlation was also seen to exist
between particle size and corresponding drug
entrapment efficiency. Actual drug content was
found to be ranging from 47.47 to 50.33 %.
Preparation method showed good reproducibility, as
indicated by analyses of actual drug content and
encapsulation efficiency carried out on each group
of three batches prepared under identical conditions.
All these results demonstrated the suitability of the
method for the preparation of the beads, using suitable mineral, with appropriate size and high encapsulation efficiency.
In vitro domperidone release studies
In vitro drug release profile of MOEG beads is
shown in Figure 4, rate and extent of drug release
from the was found to be of the order FC2 > FO2 >
FL2. The drug release was found to be slower in formulations with higher oil concentration. The slow
release of the drug from the MOEG beads may be
due to the formation of drug-oil dispersion system in
the oil pockets of the beads. The drug has to firstly
diffuse from the oil pockets into the polymer matrix
followed by transportation out of the polymeric
matrix into the dissolution medium (9). Hence,
transportation of the drug from the MOEG beads
could be attributed as a two step process, which may
be responsible for the slow drug release from the
MOEG buoyant beads of alginate. In order to investigate the mechanism of drug release, the data were
fitted to models representing zero-order, first order,
Higuchiís square root of time model and
Korsmeyer-Peppas model. The diffusion exponent
(n) value, as calculated from Korsmeyer-Peppas
model, for MOEG beads formulated using castor oil
ranged from 0.4855 to 0.5457, for olive oil 0.5391to
0.6675 and for linseed oil 0.5783 to 0.7710, respectively, indicating anomalous drug release behavior
from the beads involving a combination of swelling,
diffusion and/or erosion of matrices. Hence polymer
swelling and erosion along with formation of
hydrophobic diffusional barrier by the incorporated
oil in the MOEG beads might be playing a collective
role in retarding the release of the drug from the
beads. Higuchi model for domperidone release and
Korsmeyer-Peppas model for mechanism of drug
release from MOEG beads are shown in Figures 5
and 6, respectively (10, 11).
CONCLUSION
In conclusion, the emulsion gelation method
for the preparation of domperidone loaded MOEG
buoyant beads of alginate polymer offers flexible,
easily controllable and consistent process for
achieving the homogeneity and uniformity of beads
formation. The results demonstrated the superiority
of linseed oil over castor oil and olive oil in terms of
bead buoyancy, particle size uniformity/integrity
and drug release.
Acknowledgments
The authors are grateful to Dr. Madhu
Chitkara, Director, Chitkara Institute of Engineering
and Technology, Rajpura, Patiala, India, Dr. Ashok
Chitkara, Chairman, Chitkara Educational Trust,
Chandigarh, India and Dr. Sandeep Arora, Director,
Chitkara College of Pharmacy, Rajpura, Patiala,
India for support and institutional facilities.
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Received: 15. 02. 2010